JPS6212717A - Solid medicine containing erythromycin derivative for oral administration and manufacture - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 9-deoxo-11-deoxy-9゜11-
[imino[2-(2-methoxyethoxy)-ethylidene]oxy]-(9S)-erythromycin, (hereinafter referred to as As
-X136) and a method for producing the same.

DE-A knee 2,515.075 (British patent 41 5
20 963) describes that As-X136 is a substance with particularly excellent antibacterial activity.

In particular, when this substance is administered in the form of a solution via the gastrointestinal tract, for example intravenously, it exhibits an excellent antibacterial effect.

As-1136 has a considerable advantage over other macrolide antibiotics because it only needs to be administered once a day at a total dose of less than 500 μl. Furthermore, As-m136 is distinguished from other drugs of the same structural type, such as erythromycin, by its exceptionally high and prolonged tissue concentration.

However, the present substance A8-
Formulations for oral administration with E13(S) result in very low and generally variable tissue concentrations after administration and therefore this formulation has been deemed unsuitable for the administration of the active substance. It has been.

A pharmaceutical formulation for oral administration having As-X136,
□There was an urgent need to find and develop something that did not have the above disadvantages.

As-136 is characterized by a pronounced sensitivity to acidic media, its active substance is erythromycin.
) As with other macrolide antibiotics such as
) Normally, it decomposes within a short period of time under the action of gastric juice (pH 1.0-2.0). The main decomposition product of A8-X136 is erythromycylamine, which actually has more antibacterial activity than As-B136, but when administered orally to humans, only a small amount is absorbed and it is not microbiologically effective. To obtain adequate blood concentrations, this substance must be taken in very large doses or effective blood g concentrations cannot be obtained. This is illustrated by the values obtained for the purpose of determining the area under the plasma concentration curve. (AU
G-area on the curve).

Table 1 shows the AUG values after administration of elimellomycylamine.

Table 1 AUG value of plasma concentration after oral administration of this tablet to 7 subjects (
(approximate number).

Subject: AU (3 (mc9) up to 24 hours after taking
/mjX h )
．． Even around 5, the hydrolyzability of AS-Kl 36 is
remains unchanged. As shown in Tables 2 and 3 below, As-x
136 is...7. It is stable only near D or above.

Table 2 Single value Unaffected erythromycin base (regret) After 30 minutes After 60 minutes L3 30 104.5
55 505.5 1
00 85 Table 3 Single value No effect As-1136 (忤) 60 minutes later 1.0 10 6.0 20 6.5 20 7.0 50 7.5 80 8.0 95 As-B136 was optionally Together with other adjuvants such as carriers and disintegrants, they cannot simply be coated with lacquers that are resistant to gastric juices and release the active substance only at p) 17.0 and above. This is because - is not within such a range in the gastrointestinal tract where absorption would occur.

This is clear from the following. That is, the average - in the human intestine is in the range of 5.0 to 7.0, i.e. in the uppermost part of the intestine (-duodenum) it is 5.0 and in the lower part (colon) - , 7.0. It is also well known that the extent of absorption is quite limited in the lower part of the intestine. This is especially true for macrolide As-B136.
This applies to large molecules such as. It would not be difficult to develop reliable dosage forms for active substances such as erythromycin, which is sensitive to gastric juices. This is because this active substance is present in the upper intestine (pH approximately 5-5.5).
is meaningfully stable. In this case, it is well known to compress the active substance, for example with excipients, into tablets and to coat them with so-called gastric juice-resistant lacquers, such as acetylphthalcellulose or hyroxyprobyl methylcellulose phthalate.

After passing through the stomach, this lacquer dissolves in intestinal fluids and
: Active substance is dissolved and absorbed. This well-known principle is
:A8-B13<SK: is not applicable. This is because, as shown in Table 2, this active substance has a pH of 7.
, Only in 5, ゛□,,iOh□□Oh7, Uaah6
．． 7.0 Care 81° etc. In general, isn't the - of - achieved in the intestines? 4. □Wow. However, at this point the pharmaceutical formulation is surrounded by thick feces and therefore the extent of absorption is only modest.

The absorption of As-x136 is intricately related to the pH level in each part of the intestine and the degree of absorption in the lower intestine, which is reduced due to other reasons. As- releases the active substance at the point
This is precisely illustrated by one formulation.

(see Table 4) AUC of plasma concentrations of various drugs releasing active substances at different visits
Value (approximate number) Minimum value Maximum value zp234/j2 5.0 1.0-
56.0zp231/13 6.2-6.7
650.0-1650.0ZP234/14 7.0
-7.4 130.0- 390.0 Drug ZP 2
The composition of 34/12 is a starter core consisting of 70 parts sucrose and 30 parts corn starch powder.
Section 52, active substance 46.37%, talc 15.65%,
5.65% polyvinylpyrrolilene, 7.054% hydroxypropyl methylcellulose phthalate and 1.0% castor oil.
96%. Drug ZP 234/13 is zp 2
Starter core 24. with the same composition as in the case of 34/12.
Section 91, active substance 49.54%, talc 11.521 polyvinylpyrrolidone 6.05%, Eudragit s
4.36 elfs, Kudragit L 1.0
Consisting of 1.644% 9% castor oil and 0.91% magnesium stearate. The drug ZP 234/14 contains a starter core of the same composition as described above: 23.51 parts of active substance, 46.74 parts of talc, 11.60 parts of talc, polyvinyl fo
)'n 5.71%, Eudragit S 7.59
%, F! udragit IL 1.03%, castor oil 2.674 and magnesium stearate 0.86
It consists of 1.

(The above percentages are weight percentages, and the active substance is
It is AEI-1156. ) As shown in the table above, pH 5.0 (exit from the stomach,
Pellets coated with a lacquer that releases the active substance at a pH in the duodenum) practically do not exhibit blood concentrations with antibacterial activity. The same pellet has a pk of 46.2-6.
7 (a region in the lower duodenum towards the ileum) when covered with a membrane releasing the active substance, there is variation;
Although only a low blood concentration can be obtained, this pellet is
When covered with a membrane that releases active substances only in the range H7.0-7.4, the blood concentration again decreases significantly. With such lacquers that release active substances in the intestinal tract at a pH of 5.0, practically no blood concentration is achieved. That is, the active substance is degraded faster than it is absorbed. On the other hand, even if the active substance is released within a range (pH 7.0-7.4) where it can exist more stably, no absorption actually occurs in this part of the intestinal tract (colon), so
Not achieving blood concentration.

When releasing active substances using a lacquer that releases active substances in the intestinal tract, which has a pH in the range of 6.2 to 6.7, as shown in Table 3, decomposition proceeds faster than absorption, so it is extremely difficult to release active substances. only low blood concentrations can be obtained. In summary, it can be said that it is not possible to prepare suitable solid pharmaceutical formulations of As-z136 that are reliably absorbed using various gastric juice-resistant lacquers.

A solid pharmaceutical vehicle for oral administration containing As-x136 and ensuring high and stable blood concentrations is prepared by combining a finely separated active substance and a basic excipient in an amount of at least 2 gram equivalents of a basic excipient. It is known that a ratio of 1 mole of active substance to active substance can be obtained by thorough mixing.

This mixture may be granulated and compressed into tablets, optionally after addition of other excipients such as disintegrants, binders, lubricants, or optionally after addition of excipients, e.g. , by sugar-coating it into pellets. or,
The mixture can also be formed into briquettes, for example using a roller compactor, for granulation purposes, optionally after addition of other excipients. Alternatively, the mixture can be suspended in a fat melt such as stearyl alcohol or polyethylene glycol and then spray hardened in a cooling tower to obtain uniform small particles. The preparations such as tablets, pellets and μ granules obtained by the above procedure were then prepared at a pH of 5.
Soluble within the range of 5 to 6.8 or pH 5.5 to 6.8
It is preferably coated with a gastric juice-resistant lacquer releasing the active substance at a pH of 6.0 to 6.4.

Examples of products according to the invention are As-
u136 100. Table 5 shows the AUC values of plasma concentrations after ingestion of a mixture consisting of SF and 100 I of magnesium carbonate.

Table 5 AUO value (approximate) of plasma concentration after oral administration of As-i136 5ooI119 in tablet form to 12 subjects Subjects AUO (me9/MXh) within 24 hours after administration
) Magnesium or calcium oxides, hydroxides, or carbonates such as magnesium chloride, or sodium or potassium carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, or potassium hydroxide , hydrogen carbonate, or hydroxide. Further, strongly basic alkali metal salts such as trisodium phosphate can also be used. Particularly preferred are magnesium monocarbonate, magnesium oxide and sodium carbonate.

The active substance and the basic excipient are mixed together in a ratio of at least 1 gram mole of active substance to 2 gram equivalents of basic excipient. The upper limit for basic excipients depends on the size of the resulting pharmaceutical formulation and the physiological tolerance for the excipient;
Or either of them is determined by K. Large amounts of pharmaceutical exfoliants are difficult to administer. Generally, the upper limit for basic excipients is 20
0 gram equivalent. A ratio of 1 gram mole of active substance to 15 to 50 gram equivalents of basic excipient is desirable.

Gastric juice-resistant lacquers used include hydroxypropyl methyl cellulose phthalate, methacrylic acid and methyl methacrylate co-coated lacquers. Rimmer (Eudragit LR)
and Eudragit 8R), acetylphthalcellulose, mixtures of these lacquers, and pH 5.5-6.
Other lacquers soluble within the range of 8 are also desirable. The amount of lacquer used is such that the lacquer coating formulation lasts for 30 minutes to 2
It is enough to remain resistant to the liquid for a while. That is, small formulations, such as granules or pellets, have a resistance to gastric fluids of at least 3.
It must be resistant for 0 minutes, while larger formulations must be resistant for 2 hours. Resistance to fiK means that when this formulation was tested in artificial gastric fluid,
In practice, this means that no active substance is released within the abovementioned time period.

Addition of a disintegrant, especially in the case of large formulations, together with basic excipients ensures a rapid release of the active substance. Thus ensuring fast absorption and action. For example, in the case of tablets, disintegrants speed up the disintegration into particles. This increases the surface area of the drug while protecting the active agent, making the basic excipient susceptible to acidity for a sufficient period of time for absorption of the active agent to occur. The amount of disintegrant is calculated as a function of its action so that the core of the pharmaceutical preparation, for example a tablet core, disintegrates within one hour, preferably within 30 minutes. Suitable disintegrants include starch, Croscarmelose 8odium (
AC-DT-8QLR), Sodium Starch G4ycolate
) or crospovidone
) may be used alone or in combination with each other.

In all pharmaceutical formulations according to the invention: ′
In the range up to -7, it is important to always associate the sensitive active substance with the basic excipient. This can be achieved by compressing the mixture into tablets after optionally adding excipients such as
In particular, the disintegrants mentioned above and other conventional additives such as polyvinylpyrrolidone or lubricants such as magnesium stearate are also included. The material to be tabletted is moistened and then granulated, and the dried granules are compressed into tablets. The tablets obtained are coated according to the invention with one of the gastric juice-resistant lacquers mentioned above, for example by spraying with a suitable lacquer solution.

In addition, monoto, which is a well-mixed active substance and basic excipient,
There is also the possibility of combining an adhesive substance such as polyvinylpyrrolidone and applying this mixture to the pellet inducer core. For example, a circular sugar-coated pellet is used as the pellet oxidant core. A suspension of active substance, basic excipient and adhesive substance is then sprayed onto these pellet starter cores. The mixture described above can also be pelletized by many other known methods.

On the other hand, to obtain granules of the active substance, a well mixed mixture of the active substance, a basic excipient and other additives, such as adhesive substances, such as polyvinylpyrrolidone, is prepared in a moist state. It can be made into briquettes using a roller compactor. The coarse particles thus prepared are crushed, those of appropriate size are selected, and the remainder is returned to the roller compactor for reuse.

For example, in order to prepare particularly small and uniformly large particles for pharmaceutical suspensions, in this case diameters of 0.2 to
Although 0.5 fi particles are preferred, spray curing is preferred. In this case, the active substance is suspended in a melt together with a basic excipient and this melt is blown through a cooling tower. Suitable melts include, for example, fats or fatty alcohols with a high melting point, such as stearyl alcohol, and other substances with similar physical properties, such as polyethylene glycol, for example.

All the particles prepared by the above procedure were then mixed at pH 5.5.
Coat with a gastric juice-resistant lacquer soluble within the range of ~6.8.

After the gastric juice-resistant lacquer has dissolved in the intestinal tract, microspheres with higher basicity than the surroundings are formed around the active substance and stabilize the active substance within this range. Particles with microspheres preferentially move along the intestinal lining.

As a result of this short diffusion path, absorption of the active substance can occur with virtually no degradation. This is one advantage that this active substance has a relatively high absorption rate compared to its decomposition product, erythromycylamine.

The figure shows the dissolution of tablets prepared according to Example 1 in artificial intestinal fluid at pH 6.0 compared to tablets prepared without basic excipients. The core of the tablet, trspxx
Place in equipment and stir with paddle at 1100 rpm.

In the figure, the vertical axis shows undecomposed AB-1136 as a function of time.
shows. Curve M corresponds to the tablet prepared in Example 1, while curve B corresponds to the comparative tablet prepared without the addition of basic excipients.

The following examples are intended to illustrate the essence of the invention.

Example 1 Tablet composition: A8-z 136 100 Mg (
1) Magnesium carbonate 100~
(2) Cross-linked polyvinyl girolidone 44.5
11I9(3) Polyvinylpyrrolidone
5.0111F (4) Magnesium stearate 1.01fl;' (5) Acetyl phthalcellulose 24.811P
(6) Diptyl phthalate 1.
2 da (7) 276.51! Ig active substance (1), basic excipient (2) and disintegrant (3)
are mixed with each other in specific proportions and moistened with adhesive (4),
Dissolve in Improper Tool and then dry to granulate. After adding the lubricant (5), the material is compressed into tablets and coated by spraying with a mixture of lacquer components (6) and (7) dissolved in ethanol/methylene chloride.

Gastric juice resistant tablets are tested in a U8PXX release device (paddle method, 1100 rp, 37°C). Place the same fissure in each medium one after the other and stir.

Time Medium - Release value (regret) 1 hour
Artificial gastric fluid 1.20 1 hour Artificial intestinal fluid 4.50 15 minutes Artificial intestinal fluid 6.0 21.130 minutes
Artificial intestinal fluid 6.0 98.4 cases 2 Tablet composition: As-K 136 100 11I9 (1
) Magnesium carbonate 250~ (2
) Disintegrant, starch 44.5 WI
9(3) Polyvinylpyrrolidone 8.0
■ (4) Magnesium stearate 1
．． 0! (5) Acetyl heptal cellulose
27.7 w (6) Diptyl phthalate
1.4 da (7) 432.611 jg Tablets of this composition are prepared in a similar manner to Example 1. The emission values determined as a function of time and − are as follows. : Time Medium - Release value (regret) 1 hour
Artificial gastric fluid 1.20 1 hour Artificial intestinal fluid 4.50 15 minutes Artificial intestinal fluid 6.0 10.930 minutes
Artificial intestinal fluid 6.0 99.2 cases 3 Tablet composition: A8-E 136 100 119
(1) Magnesium oxide 175
my (2) Disintegrant, starch
65 1v (3) Fine quality cellulose
110 # (4) Polyvinylpyrrolidone 2mg (4) Magnesium stearate 2.5 NIP (5
) Acetyl 7-tal cellulose 31.8M9
(6) Diptyl phthalate 1
．． (7) Gastric juice-resistant tablets having this composition are prepared in a similar manner to Example 1. The emission values determined as a function of time and − are as follows. : Time Medium - Release value (regret) 1 hour Artificial gastric fluid 1.20 1 hour Artificial intestinal fluid 4.50 15 minutes Artificial intestinal fluid 6.00 20 minutes Artificial intestinal fluid 6.8 77.930 minutes
Artificial intestinal fluid 6.0 99.4 cases 4 Tablet composition: As-K 136 1251 #g (
1) Aluminum hydroxide 20■
(2) Calcium hydroxide 101
11011I disintegrant, starch 35 da (3) Polyvinylpyrrolidone 6
■ (4) Magnesium stearate
119 (5) Copolymer of methacrylic acid ester 18■ (6) (Kudragit L
) Triacetin 21ag(7)2
17 Da Gastric juice-resistant tablets having this composition are prepared in a similar manner to Example 1. The emission values determined as a function of time and − are as follows. : 2 hours Artificial gastric fluid 1.20 15 minutes Artificial intestinal fluid 6.2 3230 minutes Artificial intestinal fluid 6.2 96.4 cases 5 Tablet composition: As-x 136 125 If
(1) 'Sodium carbonate
125119 (2) 'Tablet disintegrating substance starch 5611? g(3) Polyvinylpyrrolidone 6111? (4
) 'Magnesium stearate
3 ■ (5) Acetyl phthalcellulose
3011F (5) ″7 Diptyl talate j, 6w (7)
``Gastric juice-resistant tablets with this composition are prepared in a similar manner to Example 1.The release values determined as a function of time and -1 are as follows: Time Medium -Release Values (2) Time Artificial gastric juice 1.20 15 minutes Artificial intestinal juice 6.0 24.330 minutes
Artificial intestinal fluid 6.0 98.2 cases 6 Pellets with As-1136: As-F! 136 2.8kg
(1) Calcium hydroxide 4.
2 kg (2) disintegrant, starch 1
．． 2kg (3) Methylcellulose
0.4 klI(4) polyethylene glycol 6
000 1.4 to 9 (5) 7-thalic acid hydroxyprobyl-methyl cellulose 0.8 yu
(6) Castor oil 0.2
Yu (7) Talc 0.4
kg (8) Mix components (1) to (5) with each other and moisten with water.

Sift the wet mass into a mesh size of 0.8 fl.
Push it out using a sieve. This extruded strip is
Round it with an elumerizer. Components (6) to (8) are dissolved or suspended in isopropanol/acetone (volume ratio 6:3), and this solution is sprayed onto the dried pellets. The emission values determined as a function of time and − are as follows. : Time Medium - Release value (regret) 2 hours Artificial gastric juice 1.20 15 minutes Artificial intestinal juice 6.4 47.530 minutes Artificial intestinal juice 6.4 96.9 cases 7 A8-x 156 granules: A8-K 136 2. 72 to 9 (1) Magnesium hydrogen carbonate 2.72 kg9
(2) Disintegrant, starch 0.95
kg(3) Polyvinylpyrrolidone 0
．． 14 kliJ (4) Cellulose acetylphthalate 3.38 k19 (5) Diptyl phthalate 0.09kliF
(6) Components (1) to (4) are mixed together and made into briquettes using a roller compactor. The material is crushed and 0.2 to 0.451 m pieces are sieved. The fine and coarse pieces are reshaped and crushed.

Particles of 0.2-0.45 mm were coated with components (5) and (6) and ethanol/methylene chloride (volume ratio 1:1) K
dissolve. The emission values determined as a function of time and − are as follows. : Time Medium - Release value (rate) 1 hour Artificial gastric fluid 1.2 <315 minutes Artificial intestinal fluid 6
．． 0 6930 minutes Artificial intestinal fluid 6.0 9
9.3 Suspension of the granules: The coated particles are mixed with specific additives and suspended in water. This suspension 203+j contains the following: gastric juice-resistant ASKi3,5 granules 919.2 citric acid
150.01! I9 sucrose
5000.0 Dasatsukarin Sodium
5.0 orange flavor
60.01R9 Xan gum 1
25.0 Da Example 8 is-z136peL/7t: Mu13-313 (51.8kg (1) Trisodium phosphate 1.2 kl
I (2) Stearyl alcohol
6.0) Cf, (3) Lactose
0.5 kg (4) Copolymer of methacrylic acid ester (ludragits) 2
．． 2 kg (5) Hydroxypropylmethylcellulose 7-talate (HP55) 0.8kl
i+ (6) Merck 3.0
kg (7) of stearyl alcohol (3) is melted at 75° C. and components (1), (2) and (4) are vigorously suspended therein. This suspension is blown through a single material phase in a cooling tower. The spray-cured particles (801 or more are within the diameter range of 0.2 to 0.5 m) are added to the lacquer components (5) and (6).
) and (7), and dissolve or suspend them in isopropanol/acetone (volume ratio 1:1) so that the fine particles do not stick together as much as possible. The emission values determined as a function of time and − are as follows. : Time Medium - Release value (time) 30 minutes Artificial gastric juice 1.2 <315 minutes Artificial intestine fi
6.5 7430 minutes Artificial intestinal fluid 6.5
99.1

[Brief explanation of drawings]

The drawing is a graph showing the solubility of the tablet according to the present invention in artificial intestinal fluid.

Claims (10)

[Claims] (1) A solid pharmaceutical preparation for oral administration containing 9-deoxo-11-deoxy-9,11-[imino[2-(2-methoxyethoxy)ethylidene]-oxy]-(9S)-erythromycin as an active substance; The active substance is thoroughly mixed with the basic excipient in a ratio of 1 mole of active substance to at least 2 gram equivalents of basic excipient, and this mixture and optionally other excipients are mixed thoroughly. 1. A pharmaceutical preparation, characterized in that the solid pharmaceutical preparation is coated with a gastric juice-resistant lacquer which releases the active substance in the pH range from 5.5 to 6.8. (2) The solid pharmaceutical preparation for oral administration according to claim 1, which contains a disintegrant. (3) The mixture of active substance and basic excipient is compressed into tablets with customary excipients and coated with a lacquer that releases the active substance in the pH range 5.5-6.8. A solid pharmaceutical preparation for oral administration according to any one of claims 1 and 2. (4) The mixture of the active substance and the basic excipient is pelletized and coated with a lacquer that releases the active substance in the pH range 5.5 to 6.8; The solid pharmaceutical preparation for oral administration according to any one of Item 2. (5) A mixture of the active substance and a basic excipient is granulated and coated with a lacquer that releases the active substance in the pH range 5.5 to 6.8. The solid pharmaceutical preparation for oral administration according to any one of Item 2. (6) Spray-cure the mixture of active substance and basic excipient into granulated spheroids and adjust the active substance to pH 5.
．． A solid pharmaceutical preparation for oral administration according to any one of claims 1 and 2 coated with a lacquer releasing in the range of 5 to 6.8. (7) A solid pharmaceutical preparation for oral administration according to any one of claims 1 to 6, which is coated with a lacquer that releases the active substance in the pH range of 6.0 to 6.4. (8) Basic excipients include magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium hydrogen carbonate, calcium hydroxide, calcium carbonate, magnesium aluminum hydroxide, magnesium aluminate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, Potassium bicarbonate, sodium hydroxide or potassium hydroxide,
Trisodium phosphate is used in a ratio of 2 to 50 gram equivalents of basic excipient per gram mole of active substance, hydroxypropyl methylcellulose phthalate, copolymers of methacrylic acid and methyl methacrylate, acetylphthalcellulose, or these compounds. a mixture of the active substance and a basic excipient, coated in such an amount that the coating remains resistant to gastric juices for up to 2 hours, and a mixture of the active substance and a basic excipient, further containing other adjuvants. A solid pharmaceutical preparation for oral administration according to any one of claims 1 to 7. (9) The solid pharmaceutical preparation for oral administration according to claim 8, wherein a mixture of different basic excipients is used as the basic excipient. (10) 9-deoxo-11-deoxy-9,11-[
Imino-[2-(2-methoxyethoxy)ethylidene]
A method for producing a solid pharmaceutical preparation for oral administration containing -oxy]-(9S)-erythromycin as an active substance, the method comprising:
The active substance is thoroughly mixed with a basic excipient in a ratio of 1 mole of active substance to at least 2 gram equivalents of basic excipient, and a) after addition of further excipients, the mixture is granulated. b) This mixture is combined with an adhesive substance and made into pellets; or c) The mixture is compressed and then crushed into granules of the desired size. or d) suspending this mixture in a melt and blowing the melt into spheroid particles of a specific diameter in a cooling tower, and the resulting formulation is then sieved to pH 5.5-6. .8 coated with a gastric juice-resistant lacquer releasing the active substance and, if desired, the particles obtained according to c) or d) are suspended in a suspending medium for the purpose of preparing a syrup. A method characterized by: